Extracellular targeted drug conjugates

Abstract

The present invention relates to, inter alia, extracellular drug conjugates (EDC) in which an antibody or other targeting agent (e.g. a targeting moiety) is linked to a drug through a linker (e.g. a non-cleavable linker). These conjugates are useful in the treatment of disease and / or as a tool in the evaluation of biological systems.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention provides drug conjugates in which an antibody or other targeting agent (e.g. a targeting moiety) is linked to a drug through a linker (e.g. a non-cleavable linker). In one embodiment, the drug acts on an extracellular target. These conjugates are useful in the treatment of disease and / or as a tool in the evaluation of biological systems. The invention relates to the fields of biology, chemistry, medicinal chemistry, medicine, molecular biology, and pharmacology.[0003]2. Description of Related Disclosures[0004]All fundamental biological processes, including development, immunity, and tumorigenesis, are related to the selective and differential expression of genes in different tissues and cell types. For example, the formation of many malignant tumors has been shown to be associated with the production and / or expression of certain specific cell surface signaling molecules. One of the goals of modern ...

AI Technical Summary

Benefits of technology

[0017]In a sixth aspect, the invention provides methods of treating a disease with an EDC of the invention in combination with one or more other th

Problems solved by technology

Unfortunately, a number of technical difficulties have been encountered with the ADC approach, including the difficulty of finding a means to link the antibody and drug where the linker is stable in the circulatory structure but “unstable” once the ADC has bound to its target or has been internalized into the target cell.

Drug release in the circulatory structure before the antibody binds its target or is internalized can lead to undesired toxicity or off target effects.

Failure to release the drug after the antibody-target binding or internalization can lead to reduced efficacy.

Together, these requirements impose considerable design constraints.

In addition, there have been no cases to date where the target for the drug is in close enough proximity to the antibody's target where both the linked drug and antibody act simultaneously.

Another difficulty encountered with the approach relates to how much active drug can be delivered to a target inside the cell by the ADC.

Another difficulty encountered with the approach relates to multidrug resistance mechanisms of internalized drugs.

Yet another drawback with the ADC approach is that the targets have been limited to targets that internalize upon ADC binding.

Complicating this even further are the cases where the target is expressed and internalization occurs, but the internalization is within compartments where drug antibody dissociation does not occur, leaving the drug ineffective.

Given all these constraints, it is not surprising that Mylotarg [the only ADC approved by the FDA for human therapeutic use (see Hamann, Bioconjug Chem, 13: 40-46, 2002)] was recently removed from the market due to limited efficacy, and no other ADC has been approved to date.

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